The translational goal of this project is to evaluate the adoptive transfer of tunnor-specific T cells derived or engineered from central memory cells to treat breast cancer. The immune system is designed to distinguish diseased from normal cells with exquisite specificity and sensitivity, and there is increasing evidence that tumor development and progression is restrained by adaptive host T cell responses to tumor-associated antigens. However, harnessing this activity to provide therapeutic benefit in breast cancer requires identifying antigens that are expressed by tumor cells and can be safely targeted, and developing methods to achieve potent and durable T cell immunity in patients. Many candidate tumor associated antigens have been discovered in breast cancer and we have focused on targeting the HER-2 oncoprotein and NY-BR-1. We have pursued the adoptive transfer of T cells specific for these antigens because this approach should allow for control ofthe specificity, function, and magnitude ofthe antitumor response, and could overcome obstacles that limit the endogenous host response, or T cell responses elicited by vaccination. The efficacy of adoptive T cell therapy in clinical trials for other human malignancies has been limited by the inability of tumor-specific effector cells that have been expanded in vitro to persist at high levels in vivo after adoptive transfer. Studies in our lab have demonstrated that the survival of adoptively transferred T cells is correlated with the differentiation state of the precursor T cell from which the T cells are derived. Effector cells isolated from central memory but not effector memory T cells provide persistent engraftment, migrate to memory T cell niches, function in vivo after adoptive transfer, and can be sustained at remarkably high levels by a short course of IL-15. This project will build on these findings and evaluate the adoptive transfer of T cells derived or engineered from central memory cells to treat breast cancer. The specific aims are: 1. To perform a phase I trial of adoptive T cell therapy with TcM-derived HER-2/neu (HER-2)-specific T cells following in vivo priming with a HER-2 peptide vaccine in patients with advanced HER-2 breast cancer 2. To engineer CD45RO* CD62L* TCM derived effector T cells through T cell receptor (TCR) gene transfer to express a TCR that targets NY-BR-1. 3. To perform a phase I study of adoptive T cell therapy with TCR modified TCMIO target NY-BR-1 in patients with advanced NY-BR-I breast cancer.